WO2001062715A1 - Novel cd23 inhibitors - Google Patents
Novel cd23 inhibitors Download PDFInfo
- Publication number
- WO2001062715A1 WO2001062715A1 PCT/GB2001/000807 GB0100807W WO0162715A1 WO 2001062715 A1 WO2001062715 A1 WO 2001062715A1 GB 0100807 W GB0100807 W GB 0100807W WO 0162715 A1 WO0162715 A1 WO 0162715A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- benzo
- ylmethanesulfonyl
- hydroxy
- compound
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to novel inhibitors of the formation of soluble human CD23 and their use in the treatment of conditions associated with excess production of soluble CD23 (s-CD23) such as autoimmune disease, inflammation and allergy.
- s-CD23 soluble CD23
- CD23 (the low affinity IgE receptor FceRII, Blast 2), is a 45 kDa type II integral protein expressed on the surface of a variety of mature cells, including B and T lymphocytes, macrophages, natural killer cells, Langerhans cells, monocytes and platelets (Delespesse et al, Adv Immunol, 49 [1991] 149-191). There is also a CD23-like molecule on eosinophils (Grangette et al, J Immunol, H3 [1989] 3580-3588). CD23 has been implicated in the regulation of the immune response (Delespesse et al, Immunol Rev, 125 [1992] 77-97).
- Human CD23 exists as two differentially regulated isoforms, a and b, which differ only in the amino acids at the intracellular N-terminus (Yokota et al, Cell, 55 [1988] 61 1-618). In man the constitutive a isoform is found only on B-lymphocytes, whereas type b. inducible by IL4, is found on all cells capable of expressing CD23.
- i-CD23 cell bound CD23
- s-CD23 well-defined soluble fragments
- s- CD23 has been implicated in the overproduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjunctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 366, [1993] 421-428).
- S-CD23 Other biological activities attributed to S-CD23 include the stimulation of B cell growth and the induction of the release of mediators from monocytes.
- elevated levels of S-CD23 have been observed in the serum of patients having B-chronic lymphocytic leukaemia (Sarfati et al. Blood, 71 [1988] 94-98) and in the synovial fluids of patients with rheumatoid arthritis (Chomarat et al, Arthritis and Rheumatism, 36 [1993] 234-242). That there is a role for CD23 in inflammation is suggested by a number of sources. First, sCD23 has been reported to bind to extracellular receptors which when activated are involved in cell-mediated events of inflammation.
- CD23 is reported to directly activate monocyte TNF, I -1, and IL-6 release (Armant et al, vol 180, J. Exp. Med. , 1005-1011 (1994)). CD23 has been reported to interact with the B2-integrin adhesion molecules, CDl lb and CDl lc on monocyte/macrophage
- compounds which inhibit the formation of S-CD23 should have twofold actions of a) enhancing negative feedback inhibition of IgE synthesis by maintaining levels of i-CD23 on the surface of B cells, and b) inhibiting the immunostimulatory cytokine activities of higher molecular weight soluble fragments (Mr 37, 33 and 29 kDa) of S-CD23.
- inhibition of CD23 cleavage should mitigate sCD23-induced monocyte activation and mediator formation, thereby reducing the inflammatory response.
- TNF ⁇ is a pro-inflammatory cytokine which is released from stimulated cells by specific cleavage of a 76-amino acid signal sequence in the inactive precursor to generate the mature form.
- the cleavage of TNF ⁇ has been reported to be carried out by a metalloprotease (Gearing, A.J.H. et al, (1994) Nature 370, 555-557; McGeehan, G.M. et al, (1994) Nature 370, 558-561; Mohler, K.M. et al, (1994) Nature 370, 218-220).
- Compounds reported to inhibit the cleavage of TNF ⁇ by the TNF processing enzyme can be broadly described as matrix metalloprotease inhibitors, particularly of the hydroxamic acid class.
- TNF ⁇ is induced in a variety of cell types in response to bacteria, endotoxin, various viruses and parasites, so that one physiological function ascribed to TNF ⁇ is a contribution to the inflammatory response to acute infection by bacteria, parasites, etc (Dinarello, CA. (1992) Immunol. 4, 133-145).
- Overproduction of TNF ⁇ has been implicated in disease states such as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). Inhibition of processing of TNF ⁇ to the mature, active form would therefore be beneficial in the treatment of these inflammatory disorders.
- TNF ⁇ may also contribute to the destruction of tissue in autoimmune disease although it is not an initiating factor in these diseases.
- TNF ⁇ antibodies have been shown to reduce the severity of disease in short term studies in rheumatoid arthritis models (Elliott, M.J., et al (1993) Arthrit. Rheum. 12. 1681 -1690; Elliott et al (1994) Lancet 344, 1 125-1 127).
- International Patent Application No. WO 97/27174 (Shionogi & Co., Ltd) and
- R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl; R! is bicyclyl or heterobicyclyl; R ⁇ is aryl. heteroaryl, heterocyclyl. alkoxy, alkyl, hydroxy, aryloxy or optionally substituted amino and n is from 0 to 3; with the provisos that when n is 0 R2 is alkyl or when n is from 1 to 3 R ⁇ is not alkyl.
- Amino referred to herein in the definition of the R ⁇ group includes amino groups substituted one or more times with (C l-6)alkyl.
- Alkyl, alkenyl alkynyl and alkoxy groups referred to herein in the definition of the R and R- group include straight, branched and cyclic groups containing up to eight carbon atoms, and are optionally substituted by one or more groups selected from the group consisting of aryl, heterocyclyl, (Cl- ⁇ )alkylthio, (C2-6)alkenylthio, (C2- 6)alkynylthio, aryloxy, arylthio, heterocyclyloxy, heterocyclylthio, (Cl-6)alkoxy, (Cl- 6)alkenyloxy, (Cl-6)alkynyloxy, aryl(Cl-6)alkoxy, aryl(C 1 -6)alkylthio, amino, mono- or di-(Cl-6)alkylamino, acylamino, sulfonylamino including Cl-6 alkylsulfonylamino, aryl(C
- Cycloalkyl and cycloalkenyl groups referred to herein in the definition of the R and R groups include groups having between three and eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl, alkenyl and alkynyl groups.
- aryl includes phenyl.
- any aryl group, including phenyl may be optionally substituted by up to five, preferably up to three substituents.
- Suitable substituents include halogen, CF3, OCF3, CN, (C ⁇ _6)alkyl, (C j_6)alkoxy, hydroxy, amino, heterocyclyl, heterocyclyl(Cl -6)alkyl, mono- and di-N-(Cl-
- aryl includes single and fused rings, of which at least one is aromatic, which rings may be unsubstituted or substituted by, for example, up to three substituents as set out above. Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
- heteroaryl suitably includes any heterocyclyl group which incorporates at least one aromatic ring (heterocyclic or carbocyclic).
- Suitable heteroaryl groups in the definition of the R group include thiophene, such as thiophen-2-yl and thiophen-3-yl.
- Suitable heteroaryl groups in the definition of the R ⁇ group include pyridyl such as 3-pyridyl and furyl such as furan-2- yi-
- heterocyclyl and heterocyclic suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
- Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
- a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
- a substituent for a heterocyclyl group is selected from halogen, (Cl- ⁇ )alkyl, (Cl- ⁇ )alkoxy, hydroxy, CF3, OCF3, CN, amino, mono-and di-N-(Cl-6)alkylamino, acylamino, acyloxy, carboxy, (Cl-6)alkoxycarbonyl, aminocarbonyl.
- Suitable heterocyclic groups include morpholino. succinimido, pyrrolidino, 2,5-dioxoimidazolidin-l-yl and N- pyrrolidone.
- bicyclyl means fused bicyclic rings suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring.
- One ring of the bicyclyl may be saturated or partially saturated.
- Suitable bicyclyl groups include naphthyl such as 2-naphthyl, tetrahydronaphthyl such as 2-tetrahydronaphthyl, and indanyl such as 2-indanyl.
- heterobicyclyl means fused bicyclic aromatic and non-aromatic rings containing up to 4 heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur.
- Each ring suitably has from 4 to 7. preferably 5 or 6, ring atoms.
- the fused bicyclic ring system may include one carbocyclic ring and one of the rings may be saturated or partially saturated.
- Suitable heterobicyclyl groups include benzothiophene such as benzothiophen-5-yl and benzothiophen-6-yl.
- Aromatic rings in bicyclyl and heterobicyclyl ring systems may be optionally substituted with up to three substituents. Suitable substituents include fluorine.
- R is isobutyl, cyclohexyl or phenyl, and/or R s 2-naphthyl, 5-benzothiophene, 2 -tetrahydronaphthyl or 2-indanyl, and/or R ⁇ is 2- methoxyethoxy, pyridin-3-yl, furan-2-yl, 5-dimethylaminofuran-2-yl, 2,5- dioxoimidazolidin-1-yl, 3-methyl-2,5-dioxoimidazolidin-l-yl, 3,4,4-trimethyl-2,5- dioxoimidazolidin-1-yl, N-morpholino, N,N-dimethylamino, N-succinimido, N- pyrrolidone or phenoxy and n is 1 or 2.
- R, Rl ,R2 and n are selected from the group consisting of the values ascribed to it in the Examples hereinbelow.
- the compound of formula (I) of the invention is selected from the group consisting of the compounds described in the Examples hereinbelow.
- the present invention provides the use of a compound of formula (I) for the production of a medicament for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders, and autoimmune disease, in which the overproduction of S-CD23 is implicated.
- the invention provides a method for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders, and autoimmune disease, in which the overproduction of S-CD23 is implicated, which method comprises the administration of a compound of formula (I), to a human or non-human mammal in need thereof.
- the invention also provides a pharmaceutical composition for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders, and autoimmune disease, in which the overproduction of S-CD23 is implicated which comprises a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.
- Particular inflammatory disorders include CNS disorders such as Alzheimer's disease, multiple sclerosis, and multi-infarct dementia, as well as the inflammation mediated sequelae of stroke and head trauma.
- the present invention provides the use of a compound of formula (I) for the production of a medicament for the treatment or prophylaxis of conditions mediated by TNF, including, but not limited to, inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, graft versus host reactions and autoimmune disease.
- the invention provides a method for the treatment or prophylaxis of conditions mediated by TNF, which method comprises the administration of a compound of formula (I), to a human or non-human mammal in need thereof.
- the invention also provides a pharmaceutical composition for the treatment or prophylaxis of conditions mediated by TNF, which comprises a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.
- a pharmaceutical composition for the treatment or prophylaxis of conditions mediated by TNF which comprises a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.
- the present inventors have surprisingly found that the compounds of the invention are potent and selective inhibitors of both CD23 processing and TNF processing, whilst having little or no activity as inhibitors of matrix metalloproteases.
- Salts of compounds of formula (I) include for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p- toluenesulphonates, phosphates, sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates. tartrates and benzoates.
- inorganic or organic acids such as hydrochlorides, hydrobromides, hydroiodides, p- toluenesulphonates, phosphates, sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates. tartrates and benzoates.
- Salts may also be formed with bases.
- Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as sodium or potassium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
- the compounds of the invention may be prepared by use of any appropriate conventional method, for example by analogy with the methods disclosed in patent publication EP-A-0 606 046.
- a further aspect of the invention provides a process for preparing a compound of formula (I) as defined hereinabove, which process comprises (a) deprotecting a compound of formula (II):
- R, R* , R ⁇ and n are as defined hereinabove, and X is a protecting group such as benzyl, t-butyldimethylsilyl or trimethylsilyl, or
- R, Rl , R ⁇ and n are as defined hereinabove, with hydro xylamine or a salt thereof, or (c) converting a compound of formula (I) to a different compound of formula
- Sulfonylchlorides can be prepared by first reacting a compound of formula RI-CH2-Z wherein R* is as described hereinabove and Z is halogen or an alkyl or arylsulfonate with sodium sulfite to give the corresponding sodium sulfonate, which can optionally be converted by tetra-n-butyl ammonium hydrogen sulfate into the corresponding tetra-n-butylammonium sulfonate salt.
- the tetra-n-butylammonium sulfonate salt may be formed by direct conversion of a compound of formula RI-CH2-Z where Z is preferably bromide, chloride or iodide under phase transfer conditions. Conversion of the sulfonate salt into the sulfonyl chloride may be achieved using phosphorus oxychloride in acetonitrile and tetrahydrothiophene- 1 , 1 - dioxide at elevated temperature (Abdellaoui et al, Synth.Commun.1995, 25(9) 1303).
- the sulfonyl chloride is prepared using a chlorinating agent such as phosphorus pentachloride or triphosgene, preferably under low temperature conditions such as -20°C or below, and preferably by addition of the sulfonate salt to the chlorinating agent.
- a chlorinating agent such as phosphorus pentachloride or triphosgene
- the isomers, including stereoisomers, of the compounds of the present invention may be prepared as mixtures of such isomers or as individual isomers.
- the individual isomers may be prepared by any appropriate method, for example individual stereoisomers may be prepared by stereospecific chemical synthesis starting from chiral substrates or by separating mixtures of enantiomers or mixtures of diastereoisomers using known methods.
- the invention provides compounds of formula (IA): (IA)
- the compounds are isolated in substantially pure form.
- an inhibitor of the formation of soluble human CD23 has useful medical properties.
- the active compounds are administered as pharmaceutically acceptable compositions.
- the compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal administration.
- compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
- a composition of the invention is in the form of a unit dose.
- Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvmylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvmylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
- the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
- the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
- Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose,
- fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- compositions of this invention may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a micro fine powder for insufflation, alone or in combination with an inert carrier such as lactose.
- the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns.
- small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
- sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
- xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH
- ACTH adrenal stimulants
- compositions may contain from 0.1% to 99% by weight, preferably from 10-60%) by weight, of the active material, depending upon the method of administration.
- a preferred range for inhaled administration is 10-99%, especially 60-99%, for example 90. 95 or 99%.
- Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device.
- Suitable metered dose aerosol formulations comprise conventional propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.
- Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg/ml of compound but more generally 0.1 to lOmg/ml, for use with standard nebulisation equipment.
- a unit dose form of a composition of the invention may contain from 0.1 to lOOOmg of a compound of the invention (0.001 to lOmg via inhalation) and more usually from 1 to 500mg, for example 1 to 25 or 5 to 500mg.
- Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from lmg to lg for a 70 kg human adult and more particularly from 5 to 500mg. That is in the range of about 1.4 x 10 ⁇ — mg/kg/day to 14 mg/kg/day and more particularly in the range of about 7 x 10 ⁇ 2 mg/kg/day to 7 mg/kg/day.
- Procedure 1 The ability of test compounds to inhibit the release of soluble CD23 was investigated by use of the following procedure.
- Plasma membranes from RPMI 8866 cells, a human Epstein-Barr virus transformed B-cell line Sarfati et al., Immunology 60 [1987] 539-547) expressing high levels of CD23 are purified using an aqueous extraction method.
- Cells resuspended in homogenisation buffer (20mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgC12. 1 mM DTT) are broken by N2 cavitation in a Parr bomb and the plasma membrane fraction mixed with other membranes is recovered by centrifugation at lO.OOOXg.
- the light pellet is resuspended in 0.2 M potassium phosphate, pH 7.2 using 2 ml per 1-3 g wet cells and the nuclear pellet is discarded.
- the membranes are further fractionated by partitioning between Dextran 500 (6.4% w/w) and polyethylene glycol (PEG) 5000 (6.4% w/w), at 0.25 M sucrose in a total of 16 g per 10-15 mg membrane proteins [Morre and Morre, BioTechniques 7, 946-957 (1989)].
- the phases are separated by brief centrifugation at lOOOXg and the PEG (upper) phase is collected, diluted 3-5 fold with 20 mM potassium phosphate buffer pH 7.4, and centrifuged at 100,000Xg to recover membranes in that phase.
- the pellet is resuspended in phosphate-buffered saline and consists of 3-4 fold enriched plasma membranes as well as some other cell membranes (e.g. lysosomes,
- sCD23 released from the membrane is determined using the El A kit from The Binding Site (Birmingham, UK) or a similar one utilising MHM6 anti-CD23 mAb [Rowe et al., Int. J. Cancer, 29, 373-382 (1982)] or another anti-CD23 mAb as the capture antibody in a sandwich El A..
- the amount of soluble CD23 made by 0.5 ug membrane protein in a total volume of 50 ul phosphate-buffered saline is measured by EIA and compared to the amount made in the presence of various concentrations of inhibitors.
- Inhibitors are prepared in solutions of water or dimethylsulfoxide (DMSO) and the final DMSO concentration is not more than 2 %.
- IC50's are determined by curve fitting as the concentration where 50 % inhibition of production of sCD23 is observed relative to the difference in sCD23 between controls incubated without inhibitor.
- Procedure 2 The ability of test compounds to inhibit collagenase was investigated using the following procedure.
- the potency of compounds to act as inhibitors of collagenase was determined by the method of Cawston and Barrett (Anal. Biochem. 99, 340-345, 1979), hereby incorporated by reference, whereby a 1 mM solution of the inhibitor being tested or dilutions thereof, was incubated at 37 °C for 18 h with collagen and human recombinant collagenase. from synovial fibroblasts cloned, expressed and purified from E. Coli, (buffered with 150 mM Tris, pH 7.6. containing 15 mM calcium chloride, 0.05% Brij 35. 200 mM sodium chloride and 0.02% sodium azide).
- the collagen was acetylated ⁇ H type 1 bovine collagen prepared by the method of Cawston and Murphy (methods in Enzymology 80, 71 1,1981)
- the samples were centrifuged to sediment undigested collagen and an aliquot of the radioactive supernatant removed for assay on a scintillation counter as a measure of hydrolysis.
- the collagenase activity in the presence of ImM inhibitor, or dilution thereof, was compared to activity in a control devoid of inhibitor and the results reported as that concentration effecting 50% of the collagenase (IC5o)-
- Step 1 Naphthalen-2-yImethanesulfonyl chloride Step 1: Sodium naphthalen-2-ylmethanesulfonate - 2-Bromomethyl-naphthalene (70g),was dissolved in dioxan(350ml) and treated with sodium sulfite (240g) in water (500ml). The mixture was heated under reflux for 30min. On cooling a white solid was obtained which was filtered off, washed with ether and dried to give the subtitle methanesulfonate salt (69g).
- Step 2 NaphthaIen-2-ylmethanesulfonyl chloride - To sodium naphthalen-2- ylmethanesulfonate (12g) in tetrahydrothiophene- 1 ,1 -dioxide (96ml) were added acetonitrile (48ml) and phosphorus oxychloride (24ml) and the mixture was heated. When the internal temperature reached 100°C unreacted starting material was filtered off and the hot filtrate was poured onto ice. A brown solid was filtered off and washed with hexane to give title compound (5.5g).
- Step 1 5-Bromomethylbenzo[b]thiophene - A solution containing 5- methylbenzo[b]thiophene (37g). N-bromosuccinimide (46g), and tetrachloromethane (400ml) was refluxed for 4 h, cooled, and filtered. The filtrate was evaporated and the resultant residue crystallised from hexane to give the subtitle compound (40g).
- Step 2 Tetra-n-butylammonium benzo[b]thiophene-5-methanesulfonate -
- the organic layer was dried (MgSO 4 ), evaporated, dissolved in THF (130ml), re-evaporated, and dissolved again in THF (130ml).
- Step 3 Benzo[b]thiophene-5-methanesulfonyl chloride - A solution of the tetra-n- butylammonium benzo[b]thiophene-5-methanesulfonate from step 2 (30g) in dichloromethane (150ml) was added to a cooled suspension of phosphorus pentachloride (8.3g) in dichloromethane (150ml) at an internal temperature of-20°C.
- Step 1 (R)-2-(Benzo[b]thiophen-5-ylmethanesulfonylamino)-2-phenylacetic acid -
- a suspension of (R)-phenylglycine (0.38g) in pyridine (5ml) and DMF (5ml) at 55°C was treated with BSTFA (1.35ml). After 30min at 55°C the solution was cooled to 0°C and a solution of benzo[b]thiophene-5-methanesulfonyl chloride (0.75g) in DMF (2ml) was added.
- Step 2 (R)-2-(Benzo[b]thiophen-5-ylmethanesulfonylamino)-2-phenylacetic acid- tert-b tyl ester- (R)-2-(Benzo[6]thiophen-5-ylmethanesulfonylamino)-2-phenylacetic acid (1.13g) was heated at reflux for 6h in toluene (30ml) containing N,N- dimethylformamide di-tert-butyl acetal (5ml) with a catalytic quantity of p- toluenesulfonic acid. The reaction was then washed with a saturated sodium hydrogen carbonate solution and brine. Evaporation of toluene and trituration with n-hexane and ether gave the subtitle compound (0.95g).
- Step 3 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesuIfonyl)[2-(2-methoxyethoxy)ethyI]- amino ⁇ -2-phenylacetic acid tert-butyl ester - (R)-2-(Benzo[b]thiophen-5- ylmethanesulfonylamino)-2-phenylacetic acid-/err-butyl-ester (0.15g) in toluene (3ml) containing diphenyl-2-pyridylphosphine (0.189g), N,N,N',N'- tetramethylazodicarboxamide (0.124g) and 2-(2-methoxyethoxy)ethanol (0.066ml) was heated to 70°C for 3h.
- Step 4 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesulfonyI)-[2-(2-methoxyethoxy)- ethyl]amino ⁇ -2-phenylacetic acid -
- the crude product from Step 3 was dissolved in trifluoroacetic acid (5ml) and after 2h evaporated from toluene (3x20ml) and toluene/water (2:1) (3x30ml).
- Step 5 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesulfonyl)-[2-(2-methoxyethoxy)- ethyl]amino ⁇ - N-hydroxy-2-phenylacetamide - (R)-2- ⁇ (Benzo[b]thiophen-5- ylmethanesulfonyl)-[2-(2-methoxyethoxy)ethyl]amino ⁇ -2-phenylacetic acid (0.13g) in DMF (2ml) was treated with HOAT (0.039g) and EDC (0.108g).
- Example 2 (R,S)- 2-[(Benzo[b]thiophen-5-ylmethanesulfonyI)(pyridin-3-yImethyl)- amino]-N-hydroxy-2-phenylacetamide
- Step 1 (R,S)-2-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(pyridin-3-yImethyl)- amino]-2-phenylacetic acid- r/-butyl-ester- (R,S)-2-(Benzo[b]thiophen-5- ylmethanesulfonylamino)-2-phenylacetic acid er -butyl ester (0.15g), prepared as for Example 1 , Step 2, was heated for 4h at 85°C in toluene (4ml) containing 3- pyridylmethanol (0.22ml), resin bound triphenylphosphine (0.5g, 3mmol/g) and N,N,N',N'-
- Step 2 (R,S)-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(pyridin-3-ylmethyI)amino]- 2-phenyIacetic acid -
- the crude product from Step 1 was dissolved in 95% trifluoroacetic acid/ water (5ml) and after 4h evaporated from toluene (3x20ml) and toluene/water (2: 1) (3x30ml).
- Step 3 (R,S)- 2-[(Benzo[b]thiophen-5-ylmethanesuIfonyI)(pyridin-3-ylmethyl)- amino]-N-hydroxy-2-phenylacetamide - (R,S)-[(Benzo[b]thiophen-5- ylmethanesulfonyl)(pyridin-3-ylmethyl)amino]-2-phenylacetic acid (0.12g) was treated with HOAT (0.037g) and EDC (0.095g). After lOmin this solution was added over 0.75h to a mixture of hydroxylamine hydrochloride (0.097g) and N-methylmorpholine
- Step 1 (R)-2-CyclohexyI-2-[(furan-2-ylmethyl)amino]acetic acid- (R)- cyclohexylglycine (0.95g) in DMF (15ml) was treated with BSTFA (2ml) and 2-furyl aldehyde (0.5ml). After 3h NaB ⁇ CN on resin (0.7g, 3.64mmol/g) was added and the reaction stirred for 18h. The reaction was filtered and concentrated, and re-evaporated from toluene (3x). The residue was treated with methanol (20ml) and the precipitate filtered off to give the subtitle compound (0.4g).
- Step 2 (R)-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(furan-2-ylmethyl)amino]-2- cyclohexylacetic acid - (R)-2-Cyclohexyl-2-[(furan-2-ylmethyl)amino]acetic acid (0.28g) was treated as for Example 1, Step 1 to give the subtitle compound (0.18g).
- Step 3 (R)-2-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(furan-2-ylmethyl)amino]-2- cyclohexyl-N-hydroxy-acetamide - (R)-[(Benzo[b]thiophen-5- ylmethanesulfonyl)(furan-2-ylmethyl)amino]-2-cyclohexylacetic acid (0.18g) in DCM (2.5ml) at 0°C under argon was treated with oxalyl chloride (0.038ml) and DMF (0.035ml).
- Step 1 (R)-4-MethyI-2-(naphthalen-2-ylmethanesulfonylamino)pentanoic acid tert- butyl ester - (D)- Leucine tert-buyl ester hydrochloride (0.47g) in dry DMF (3ml) was treated with diisopropylethylamine (0.72ml) followed by a solution of naphthalen-2- ylmethanesulfonyl chloride (0.5g) in dry DMF (1.5ml). After stirring at rt for 2h the reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and water.
- Step 2 (R)-4-Methyl-2-[(naphthalen-2-ylmethanesulf nyl)(pyridin-3- ylmethy ⁇ )amino]pentanoic tert-butyl ester -
- Step 3 (R)-4-Methyl-2-[(naphthalen-2-ylmethanesulfonyl)(pyridin-3- ylmethyl)amino]pentanoic acid - (R)-4-Methyl-2-[(naphthalen-2- ylmethanesulfonyl)(pyridin-3-ylmethyl)amino]pentanoic tert-butyl ester (0.17g) was taken up in acetic acid (6ml), treated with 4M HC1 (3ml) and left stirring overnight. The mixture was concentrated to dryness (bath temperature 50°C) and the residue was was triturated with ether to give the subtitle compound as a white solid (0.095g).
- Step 4 (R) - N-(tert-Butyldimethylsilyloxy-4-methyI-2-[(naphthale ⁇ -2- ylmethanesulfonyl)(pyridin-3-ylmethyl)amino]pentanoic acid amide -
- a solution of (R)-4-methyl-2-[(naphthalen-2-ylmethanesulfonyl)(pyridin-3- ylmethyl)amino]pentanoic acid (25mg) in dry DCM (1ml) was cooled to 0°C and treated with 0-(tert-butyldimethvlsilyl)hydroxylamine (13mg) in dry DCM (0.5ml) followed by EDC methiodide (26mg) in dry DCM (0.5ml).
- Step 5 (R) - N-Hydroxy-4-methyl-2-[(naphthalen-2-ylmethanesulfonyl)(pyridin-3- ylmethyl)amino]pentanoic acid amide -
- a solution of N-(tert-butyldimethylsilyloxy-4- methyl-2-[(naphthalen-2-ylmethanesulfonyl)(pyridin-3-ylmethyl)amino]pentanoic acid amide 15mg) in dry THF (0.5ml) was treated with TBAF (0.04ml of a 1M solution in THF) and left stirring for 30min.
- Step 1 (R)-2-(Benzo[ ⁇ ]thiophene-5-ylmethanesulfonylamino)-4-methyl-pentanoic acid tert-butyl ester - (D)- Leucine tert-buyl ester hydrochloride (0.906g) was stirred with BSTFA (3ml) in dry DMF/pyridine (1 : 1 by vol; 6ml) at rt until homogeneous. The reaction was then cooled to 0°C and benzo[&]thiophen-5-ylmethanesulfonyl chloride
- Step 2 (R)-2-[(2-Allyloxyethyl)(benzo[Z>]thiophen-5-ylmethanesulfonyl)-amino]-4- methyl-pentanoic acid tert butyl ester - (R)-2-(Benzo[6]thiophene-5- ylmethanesulfonylamino)-4-methyl-pentanoic acid ester (0.695g) was stirred in dry toluene ( 15ml) with 2-allyloxyethanol (0.41 ml) and triphenyl phosphine resin (3mmol/g loading, 1.739g) under an argon atmosphere.
- N,N,N',N'- tetramethylazodicarboxamide (0.662g) was then added portionwise and the reaction heated to 65°C for 3h and then stirred at rt overnight.
- the reaction mixture was filtered through celite and the filtrate evaporated to a brown crude which was chromatographed (silica-gel, step gradient 0-10% ethyl acetate/hexane) to yield the subtitle product as a clear oil (0.702g).
- Step 3 (R)-2-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(2-hydroxyethyl)-amino]-4- methylpentanoic acid tert-butyl ester - (R)-2-[(2-AIlyloxyethyl)-(benzo[ ⁇ ]thiophen-5- ylmethanesulfonyl)amino]-4-methylpentanoic acid tert butyl ester (0.702g) and tetrakis(triphenylphosphine)palladium (0.36g) were stirred in acetic acid (15ml) under argon at 80°C for 3h and then left to stand at rt overnight. The reaction mixture was concentrated, and the crude product was chromatographed (silica-gel, step gradient 0- 20%) ethyl acetate/hexane) to yield the subtitle compound as a yellow oil (0.398g).
- Step 4 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesulfonyI)[2-(2,5-dioxo-imidazoIidin-l- yl)ethyl]amino ⁇ -4-methylpentanoic acid tert-butyl ester - (R)-2-[(Benzo[b]thiophen-5- ylmethanesulfonyl)(2-hydroxyethyl)amino]-4-methyl-pentanoic acid tert-butyl ester (0.217g) was stirred in dry benzene (3ml) with imidazolidin-2,4-dione (0.073g) under argon.
- Step 5 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesulfonyl)[2-(2,5-dioxo-imidazolidin-l- yl)ethyl]amino ⁇ -4-methylpentanoic acid - (R)-2- ⁇ (Benzo[b]thiophen-5- ylmethanesulfonyl)[2-(2,5-dioxo-imidazolidin-l-yl)ethyl]-amino ⁇ -4-methylpentanoic acid tert-butyl ester (0.074g) was stirred in TF A/water (95%o TFA, 10ml) for 2h. The reaction mixture was then evaporated and co-evaporated with toluene to yield the subtitle compound as a yellow oil (0.062g).
- Step 6 (R)-2- ⁇ (Benzo[/)]thiophen-5-ylmethanesulfonyl)[2-(2,5-dioxo-imidazolidin-l- yl)ethyl]amino ⁇ -4-methyl-/V-hydroxy-pentanamide - (R)-2- ⁇ (Benzo[b]thiophen-5- ylmethanesulfonyl)[2-(2.5-dioxo-imidazolidin- l-yl)ethyl]-amino ⁇ -4-methylpentanoic acid (0.062g) was dissolved in dry DCM (2.5ml) and cooled to 0°C under argon.
- Oxalyl chloride (0.014ml) was then added, dropwise, followed by DMF (0.01 1ml) added dropwise. The resultant mixture was stirred at 0°C for 30 min.
- hydroxylamine hydrocloride (0.037g) was stirred in THF/water (4ml THF, 1ml water) at 0°C.
- Diethylaminomethyl polystyrene resin (3.2mmol/g, 0.50 lg) was then added and the reaction stirred at 0°C for 20 min.
- the solution of acid chloride was then added to the hydroxylamine solution, dropwise at 0°C. The reaction was allowed to warm to rt and stirred overnight.
- Step 1 (R)-2-(Benzo[b]thiophen-5-ylmethanesulfonylamino)-2-phenylacetic acid tert-butyl ester -
- the subtitle compound was prepared from (R)-2-(benzo[b]thiophen-5- ylmethanesulfonylamino)-2-phenylacetic acid using the procedure described in Example 1, step 2.
- Step 2 (R)-2-[(2-AHyloxyethyl)(benzo[ ⁇ ]thiophen-5-ylmethanesulfonyI)-amino]-2- phenylacetic acid tert-butyl ester -
- the subtitle compound was prepared from (R)-2- (benzo[b]thiophen-5-ylmethanesulfonylamino)-2-phenylacetic acid tert-butyl ester using the procedure desribed in Example 16, step 2.
- Step 3 (R)-2-[(Benzo[b]thiophen-5-ylmethanesulfonyl)(2-hydroxyethyl)amino]-2- phenylacetic acid tert-butyl ester -
- the subtitle compound was prepared from (R)-2-[(2- allyloxyethyl)(benzo[6]thiophen-5-ylmethanesulfonyl)amino]-2-phenylacetic acid tert- butyl ester using the procedure described in Example 16, step 3.
- Step 4 (R)-2- ⁇ (Benzo[b]thiophen-5-ylmethanesulfonyI)[2-(3-methyI-2,5-dioxo- imidazolidin-l-yl)ethyI]amino ⁇ -7V-hydroxy-2-phenylacetamide.
- Analytical chiral HPLC analysis was carried out on a Chiralpak AD column using n- hexane/ethanol 50:50 v/v as eluant at a flow rate of lml/min.
- Preparative chiral HPLC separations were carried out on a Chiralpak AD 250mm x 20mm i.d. column, using n- hexane/ethanol 50:50 v/v as eluant at a flow rate of 17.0ml/min.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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JP2001561725A JP2003523994A (en) | 2000-02-24 | 2001-02-23 | New CD23 inhibitor |
AU2001233965A AU2001233965A1 (en) | 2000-02-24 | 2001-02-23 | Novel cd23 inhibitors |
EP01906007A EP1265855A1 (en) | 2000-02-24 | 2001-02-23 | Novel cd23 inhibitors |
Applications Claiming Priority (4)
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GB0004414.9 | 2000-02-24 | ||
GB0004414A GB0004414D0 (en) | 2000-02-24 | 2000-02-24 | Novel compounds |
GB0031271A GB0031271D0 (en) | 2000-12-21 | 2000-12-21 | Novel compounds |
GB0031271.0 | 2000-12-21 |
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WO2001062715A1 true WO2001062715A1 (en) | 2001-08-30 |
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PCT/GB2001/000807 WO2001062715A1 (en) | 2000-02-24 | 2001-02-23 | Novel cd23 inhibitors |
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US (1) | US20030134880A1 (en) |
EP (1) | EP1265855A1 (en) |
JP (1) | JP2003523994A (en) |
AU (1) | AU2001233965A1 (en) |
WO (1) | WO2001062715A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004113298A1 (en) * | 2003-06-19 | 2004-12-29 | Celltech R & D Limited | Hydroxamate sulfonamides as cd23 shedding inhibitors |
WO2004113312A1 (en) * | 2003-06-19 | 2004-12-29 | Celltech R & D Limited | Hydroxamate sulfonamides as cd23 shedding inhibitors |
US7314877B2 (en) | 2003-03-07 | 2008-01-01 | Kowa Co., Ltd. | Benzofuran derivative |
CN109526218A (en) * | 2016-03-31 | 2019-03-26 | 富士胶片富山化学株式会社 | The preparation method of 5- bromomethyl -1- benzothiophene |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005073180A1 (en) * | 2003-12-25 | 2005-08-11 | Kureha Corporation | Hydroxamic acid derivative and age generation inhibitor containing the derivative |
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EP0606046A1 (en) * | 1993-01-06 | 1994-07-13 | Ciba-Geigy Ag | Arylsulfonamido-substituted hydroxamic acids |
WO1996002240A2 (en) * | 1994-07-13 | 1996-02-01 | Smithkline Beecham P.L.C. | Use of inhibitors of human s-cd23 |
WO1998042659A2 (en) * | 1997-03-26 | 1998-10-01 | Smithkline Beecham Plc | Aryl- or heteroarylsulfonamide substituted hydroxamic acid derivates, process for their preparation and their use as pharmaceuticals |
WO1999040080A1 (en) * | 1998-02-06 | 1999-08-12 | Darwin Discovery Limited | Hydroxamic and carboxylic acid derivatives |
EP0950656A1 (en) * | 1996-01-23 | 1999-10-20 | Shionogi & Co., Ltd. | Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same |
WO1999067201A1 (en) * | 1998-06-22 | 1999-12-29 | Smithkline Beecham Plc | Hydroxamic acid derivatives as inhibitors of the production of human cd23 and of the tnf release |
-
2001
- 2001-02-23 JP JP2001561725A patent/JP2003523994A/en active Pending
- 2001-02-23 EP EP01906007A patent/EP1265855A1/en not_active Withdrawn
- 2001-02-23 US US10/204,570 patent/US20030134880A1/en not_active Abandoned
- 2001-02-23 WO PCT/GB2001/000807 patent/WO2001062715A1/en not_active Application Discontinuation
- 2001-02-23 AU AU2001233965A patent/AU2001233965A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0606046A1 (en) * | 1993-01-06 | 1994-07-13 | Ciba-Geigy Ag | Arylsulfonamido-substituted hydroxamic acids |
WO1996002240A2 (en) * | 1994-07-13 | 1996-02-01 | Smithkline Beecham P.L.C. | Use of inhibitors of human s-cd23 |
EP0950656A1 (en) * | 1996-01-23 | 1999-10-20 | Shionogi & Co., Ltd. | Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same |
WO1998042659A2 (en) * | 1997-03-26 | 1998-10-01 | Smithkline Beecham Plc | Aryl- or heteroarylsulfonamide substituted hydroxamic acid derivates, process for their preparation and their use as pharmaceuticals |
WO1999040080A1 (en) * | 1998-02-06 | 1999-08-12 | Darwin Discovery Limited | Hydroxamic and carboxylic acid derivatives |
WO1999067201A1 (en) * | 1998-06-22 | 1999-12-29 | Smithkline Beecham Plc | Hydroxamic acid derivatives as inhibitors of the production of human cd23 and of the tnf release |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7314877B2 (en) | 2003-03-07 | 2008-01-01 | Kowa Co., Ltd. | Benzofuran derivative |
WO2004113298A1 (en) * | 2003-06-19 | 2004-12-29 | Celltech R & D Limited | Hydroxamate sulfonamides as cd23 shedding inhibitors |
WO2004113312A1 (en) * | 2003-06-19 | 2004-12-29 | Celltech R & D Limited | Hydroxamate sulfonamides as cd23 shedding inhibitors |
CN109526218A (en) * | 2016-03-31 | 2019-03-26 | 富士胶片富山化学株式会社 | The preparation method of 5- bromomethyl -1- benzothiophene |
RU2733381C2 (en) * | 2016-03-31 | 2020-10-01 | Тояма Кемикал Ко., Лтд. | Method of producing 5-(bromomethyl)-1-benzothiophene |
CN109526218B (en) * | 2016-03-31 | 2021-07-06 | 富士胶片富山化学株式会社 | Preparation method of 5-bromomethyl-1-benzothiophene |
US11236062B2 (en) | 2016-03-31 | 2022-02-01 | Fujifilm Toyama Chemical Co., Ltd. | Method for producing 5-(bromomethyl)-1-benzothiophene |
Also Published As
Publication number | Publication date |
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EP1265855A1 (en) | 2002-12-18 |
US20030134880A1 (en) | 2003-07-17 |
AU2001233965A1 (en) | 2001-09-03 |
JP2003523994A (en) | 2003-08-12 |
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